Epithelial cells of most organs typically express the ErbB2 (HER2) receptor tyrosine kinase at low levels. However, in several types of carcinomas, ErbB2 expression is strongly enhanced, often as a result of gene amplification. Due to this preferential expression in many tumors of epithelial origin, its accessibility from the extracellular space, and its involvement in the transformation process, the ErbB2 receptor tyrosine kinase is a preferred target for directed cancer therapy.
Based on a truncated Pseudomonas exotoxin A derivative lacking the toxin's endogenous cell binding domain, a recombinant toxin was developed that employs a single-chain Fv antibody fragment of the ErbB2-specific monoclonal antibody FRP5 for targeting of the toxin to ErbB2 (1). In in vitro cell killing experiments, this bacterially expressed scFv(FRP5)-ETA molecule displayed potent antitumoral activity against a wide range of established and primary human tumor cells, including breast and ovarian carcinomas (1-3), squamous cell carcinomas (4, 5) and prostate carcinomas (6). In experimental animals scFv(FRP5)-ETA effectively inhibited growth of established human tumor xenografts (1, 3-5) and murine and rat tumor cells stably transfected with human c-erbB2 constructs (7, 8). In cancer patients, intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions of ErbB2 expressing tumors resulted in a response rate of 60%, with complete regression of injected tumor nodules observed in 40%, and partial reduction in the size of injected tumors in another 20% of patients (9). In a recent phase I clinical study, maximum tolerated dose (MTD), dose limiting toxicity and pharmacokinetic parameters of intravenously injected scFv(FRP5)-ETA were determined (10). Thereby three out of 18 patients showed stable disease, and in another three patients clinical signs of activity in terms of signs and symptoms were observed.